This project is closely related to the overall research goal of this program project, namely to define the behavioral and biomedical correlates of the clinical course of a defined group of subjects with SDAT (or in this project, with neuropathologically proven Alzheimer's disease) in comparison with the course of healthy aging in non-demented subjects. The specific goals of the project can be expressed as two questions (1) What pattern of pathology is characteristic of the earliest stage of Alzheimer's disease? (2) what is the relationship between the patterns of tangles and placques seen in healthy aging and in the earliest, very mild stage of dementia? To address these questions, the distribution and density of neurofibrillary tangles, amyloid placques and related immunohistochemical markers (e.g. with antibodies counted in serial sections cut through the ventral forebrain from a range of carefully assessed non-demented and demented elderly cases. The presence or level of dementia in these cases will be determined in the clinical core, either by pre-mortem assessment , or by a retrospective, post-mortem interview with a closely related collateral source (usually a spouse or adult child). Because results from the previous grant period indicate that he earliest pathological changes related to Alzheimer's disease must be found in cases that have not yet shown any clinically detectable dementing change, emphasis will be placed on very old non-demented cases. In these cases special attention will be given to small patches of "primitive" or "diffuse" placques in the temporal or orbital neocortex that were identified in non-demented cases during the previous grant period, and which may represent the earliest deposition of amyloid. To examine a possible link between early plaque and tangle formation, immunohistochemistry with antibodies against tau and related proteins (e.g. the antibody Alz-50) will be used to stain the region of plaques for altered neurites ("neuropil threads") that might represent an early neurotoxic reaction to amyloid deposition.